Bcl-2 is a critical mediator of intestinal transformation.

Nat Commun 2016 Mar 9;7:10916. Epub 2016 Mar 9.

Cancer Research UK, Cambridge Institute, University of Cambridge, Robinson Way, Cambridge CB2 0RE, UK.

Intestinal tumour formation is generally thought to occur following mutational events in the stem cell pool. However, active NF-κB signalling additionally facilitates malignant transformation of differentiated cells. We hypothesized that genes shared between NF-κB and intestinal stem cell (ISCs) signatures might identify common pathways that are required for malignant growth. Here, we find that the NF-κB target Bcl-2, an anti-apoptotic gene, is specifically expressed in ISCs in both mice and humans. Bcl-2 is dispensable in homeostasis and, although involved in protecting ISCs from radiation-induced damage, it is non-essential in tissue regeneration. Bcl-2 is upregulated in adenomas, and its loss or inhibition impairs outgrowth of oncogenic clones, because Bcl-2 alleviates apoptotic priming in epithelial cells following Apc loss. Furthermore, Bcl-2 expression in differentiated epithelial cells renders these cells amenable to clonogenic outgrowth. Collectively, our results indicate that Bcl-2 is required for efficient intestinal transformation following Apc-loss and constitutes a potential chemoprevention target.

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http://dx.doi.org/10.1038/ncomms10916DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4786877PMC
March 2016
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